Aromatic benzamido compounds, their preparation and their use in human or veterinary medicine or in cosmetic preparations

ABSTRACT

An aromatic benzamido compound having the formula ##STR1## wherein R 1  represents --CH 2  OH, --CHOHCH 3  or --COR 5 , 
     R 5  represents hydrogen, lower alkyl, or --OR 6  or ##STR2## R 6  represents hydrogen, lower alkyl or mono- or polyhydroxyalkyl, r&#39; and r&#34; represent hydrogen, lower alkyl, mono or polyhydroxyalkyl, aryl or benzyl optionally substituted, the residue of an amino acid or aminated sugar or taken together form a heterocycle, 
     R 2  represents an α,α&#39;-disubstituted alkyl having 4-12 carbon atoms or mono or polycyclic cycloalkyl having 5-12 carbon atoms, the linking carbon of which is quaternary, 
     R 3  represents hydrogen or alkyl having 1-10 carbon atoms, and 
     R 4  represents a hydrogen, lower alkyl or hydroxy, and 
     the salts of this aromatic benzamido compound when R 6  represents hydrogen.

The present invention relates to new aromatic benzamido derivatives, aprocess for their preparation and their use in human and veterinarymedicine and in cosmetic compositions.

These new aromatic benzamido derivatives are usefully employed in thetopical and systemic treatment of dermatologic ailments linked to akeratinization disorder (differentiation-proliferation) and dermatologicdiseases, or others, having an inflammatory and/or immunoallergiccomponent and in degenerative conjunctive tissue diseases, as well as anantitumoral activity. Besides, these derivatives can be used in thetreatment of atophies, be they cutaneous or respiratory, and inrheumatoid psoriasis.

The compounds of the present invention are also useful in the field ofophthalmology, principally in the treatment of corneopathies.

The aromatic benzamido derivatives in accordance with the presentinvention have the following formula ##STR3## wherein R₁ represents--CH₂ OH, --CHOHCH₃ or --COR₅, ##STR4## R₆ represents hydrogen, loweralkyl or mono- or R₅ represents hydrogen, lower alkyl, --OR₆ or

R₆ represents hydrogen, lower alkyl or mono- or polyhydroxy alkyl,

r' and r" represent hydrogen, lower alkyl, mono or polyhydroxy alkyl,aryl or benzyl optionally substituted, the residue of an amino acid oran aminated sugar or, when taken together they form a heterocycle,

R₂ represents an α, α'-disubstituted alkyl radical having 4-12 carbonatoms or a mono or polycyclic cycloalkyl radical having 5-12 carbonatoms wherein the linking carbon atom thereof is quaternary,

R₃ represents hydrogen or alkyl having 1-10 carbon atoms, and

R₄ represents hydrogen, lower alkyl or hydroxy, and

the salts of said aromatic benzamido derivatives of formula I when R₆represents hydrogen.

When the compounds of the present invention are provided in the form ofsalts, the salts are salts of an alkali metal or alkaline earth metal oreven of zinc or an organic amine.

By lower alkyl radical is meant a radical having from 1 to 6 carbonatoms, principally methyl, ethyl, isopropyl, butyl and tert.butyl.

By monohydroxyalkyl radical is meant a radical having 2 or 3 carbonatoms, principally 2-hydroxyethyl, 2-hydroxypropyl or 3-hydroxypropyl.

By polyhydroxyalkyl is meant a radical containing from 3 to 6 carbonatoms and from 2 to 5 hydroxyl groups, such as 2,3-dihydroxypropyl,2,3,4-trihydroxybutyl, 2,3,4,5-tetrahydroxypentyl or the residue ofpentaerythritol.

By aryl radical is meant a phenyl radical optionally substituted byhalogen, hydroxy or a nitro function.

By αα'-disubstituted radical having 4 to 12 carbon atoms is meant atert.butyl radical, 1,1-dimethyl propyl, 1-methyl-1-ethyl propyl,1-methyl-1-ethyl hexyl or 1,1-dimethyl decyl.

By mono or polycyclic cycloalkyl radical having 5 to 12 carbon atomswhose linking carbon atom is quaternary, is meant 1-methyl cyclohexyl or1-adamantyl.

By the residue of an amino acid is meant a residue derived, for example,from lysine or glycine.

By residue of an aminated sugar is meant a residue derived for examplefrom glucosamine, galactosamine or mannosamine.

When the radicals r' and r" together form a heterocycle, it ispreferably piperidino, piperazino, morpholino, pyrrolidino or4-(2-hydroxyethyl)-piperazino.

Representative aromatic benzamido derivatives of formula I, above,include in particular:

4-[3-(1-adamantyl)-4-methoxy benzamido]benzoic acid,

4-[3-(1-adamantyl)-4-methoxy benzamido]methyl benzoate,

N-[4-[3-(1-adamantyl)-4-methoxy benzamido]benzoyl]ethylamine,

4-[3-(1-adamantyl)-4-hydroxy benzamido]benzoic acid,

4-[3-(1-adamantyl)-4-hydroxy benzamido]methyl benzoate,

4-[3-(1-methylcyclohexyl)-4-methoxy benzamido]benzoic acid,

4-[3-(1-methylcyclohexyl)-4-methoxy benzamido]ethyl benzoate,

4-[3-(1-adamantyl)-4-declyoxy benzamido]benzoic acid,

4[3-(1-adamantyl)-4-declyoxy benzamido]methyl benzoate,

4-[3-(1-adamantyl)-4-hexyloxy benzamido]benzoic acid,

4-[3-(1-adamantyl)-4-hexyloxy benzamido]methyl benzoate,

4-[3-(1,1-dimethyl decyl)-4-methoxy benzamido]benzoic acid,

4-[3-(1,1-dimethyl decyl)-4-methoxy benzamido]methyl benzoate,

4-(3-tert.butyl-4-methoxy benzamido) benzoic acid,

4-(3-tert.butyl-4-methoxy benzamido) methyl benzoate,

N-[4-[3-(1-adamantyl)-4-methoxy benzamido]-benzoyl]pyrrolidine,

N-[4-[3-(1-adamantyl)-4-methoxy benzamido]-benzoyl]piperidine,

N-[4-[3-(1-adamantyl)-4-methoxy benzamido]benzoyl]morpholine,

N-[4-[3-(1-adamantyl)-4-methoxy benzamido]benzoyl]tert. butylamine,

N-[4-[3-(1-adamantyl)-4-methoxy benzamido]benzoyl]ethylamine,

N0[4-[3-(1-adamantyl)-4-methoxy benzamido]benzoyl]aniline,

N-[4-[3-(1-adamantyl)-4-methoxy benzamido]benzoyl]benzylamine,

4-[3-(1-adamantyl)-4-methoxy benzamido]2-hydroxyethyl benzoate,

N-(4-acteylphenyl)-3-(1-adamantyl)-4-methoxy benzamide,

N-[4-(1-hydroxyethyl)phenyl]-3-(1-adamantyl)-4-methoxy benzamide,

N-[4-[3-(1-adamantyl)-4-methoxy benzamido]benzoyl]2-hydroxyethylamide,and

2-hydroxy-4-[3-(1-adamantyl)-4-methoxy benzamido]methyl benzoate.

The present invention also relates to a process for preparing thecompounds of formula I in accordance with the following reaction scheme:##STR5##

The principal step of this process comprises reacting in an anhydrousmedium, in an organic solvent, which is preferably tetrahydrofuran, andin the presence of a tertiary amine, an activated form of a substitutedbenzoic acid, for example, an acid chloride (1) with an aminatedcompound of formula (2), the reaction being carried out at ambienttemperature and with stirring.

Starting with ester (Ia) the corresponding acid (Ib) is produced bysaponification, which acid can then be activated, for example, with theaid of N,N'-carbonyl diimidazole (CDI) or by conversion into the acidchloride, and then transformed into the amide of formula (Ic) byreaction with an amine of the formula ##STR6## (r' and r" having themeanings given above).

When R₆ represents a monohydroxy or polyhydroxy radical it is preferableto prepare the acid (Ib) starting with the methyl ester (Ia) (R₆ =--CH₃)and then to esterify the resulting acid into the ester of a selectedmono or polyhydric alcohol in accordance with known methods.

The compounds in which R₁ =--CH₂ OH, and --CHOHCH₃ are obtained in aconventional manner by reduction, respectively, of the correspondingesters and ketones.

The present invention also relates to a medicine comprising thecompounds of formula I, such as defined above.

These compounds exhibit excellent activity in the inhibition test ofornithine decarboxylase in nude rats after induction, by "tapestripping" (M. Boucher et al, DERMATOLOGIA, 169, No. 4, 1984). This testis recognized as a measure of the inhibitory activity of certaincompounds on cellular proliferation phenomena.

These compounds are particularly appropriate for treating dermatologicailments linked to a keratinization disorder(differentiation-proliferation) as well as dermatologic diseases, orothers, having an inflammatory and/or immunoallergic componentprincipally:

acnes vulgaris, comedons or polymorphs, solar senile acne and medicinalor professional acne,

extensive and/or severe forms of psoriasis, and other keratinizationdisorders, and principally ichtyoses and ichtyosis-like conditions,

Darier malady,

palmo-plantar keratodermies,

leucoplasies and leucoplasi-like states, lichen plan, and

all malignant or benign dermatologic proliferations, severe orextensive.

The are also active in the treatment of tumors, of rheumatoid psoriasis,cutaneous or respiratory atrophies as well as in certain ophthalomogicproblems relating to corneopathies.

The present invention also relates to a medicinal composition containingat least one compound of Formula I, such as defined above, or one of itssalts.

The present invention thus relates to a new medicinal composition,intended for the treatment of the above mentioned disorders, comprisingin a pharmaceutically acceptable vehicle or support at least onecompound of Formula I and/or one of its salts.

The compounds according to the present invention exhibit good stabilityto light and oxygen.

The compounds according to the invention are generally administered at adaily dosage of about 0.01 mg/kg to 5 mg/kg of body weight.

As the vehicle or carrier for these compositions, any conventionalvehicle can be employed, the active compound being found either in thedissolved state, or in the dispersed state, in said vehicle.

The administration of the compounds of the present invention can beeffected enterally, parenterally, topically or ocularly.

When administered enterally, the medicines can be provided in the formof tablets, gelules, lozenges, syrups, suspensions, solutions, powders,granules or emulsions.

When administered parenterally, the medicinal compositions can beprovided in the form of solutions or suspensions for perfusion orinjection.

When administered topically, the pharmaceutical compositions, based onthe compounds of the present invention, can be provided in the form ofointments, tinctures, creams, salves, powders, pads, impregnatedtampons, solutions, lotions, gels, sprays, or suspensions.

These compositions for topical administration can be provided eitherunder anhydrous form or in aqueous form according to clinicalindications.

When administered ocularly, the composition is provided principally inthe form of an eyewash.

These compositions contain at least one compound of Formula I, asdefined above, or one of its salts, in an amount, preferably, between0.0001 and 5 percent by weight based on the total weight of thecomposition.

The compounds of Formula I, according to the present invention, are alsouseful in the cosmetic field, in particular, in body and hair hygienecompositions and principally for the treatment of skin having acnetendencies, to improve the growth of hair, to combat hair loss, tocombat against an oily appearance of the skin or hair, in the protectionagainst the harmful effects of the sun or in the treatment ofphysiologically dry skin.

The present invention thus relates to a cosmetic composition containing,in a cosmetically acceptable vehicle, at least one compound of Formula Ior one of its salts, this composition being provided principally in theform of a lotion, gel, soap or shampoo.

The concentration of the compound of Formula I in these cosmeticcompositions is between 0.0001 and 0.1 percent by weight and,preferably, between 0.001 and 0.01 weight percent, based on the totalweight of the composition.

The medicinal and cosmetic compositions according to the invention cancontain inert or even pharmacodynamic or cosmetically active additivesand principally: hydrating agents such as thiamorpholinone and itsderivatives or urea; anti-seborrheic or anti-acne agents such asS-carboxy methylcysteine, S-benzyl methylcysteamine, their salts andtheir derivatives, tioxolone or benzoyl peroxide; antibiotics such aserythromycin and its esters, neomycin, tetracyclines or4,5-polymethylene-3-isothiazolinones; agents promoting the growth ofhair such as "Minoxidil" (2,4-diamino-6-piperidino-pyrimidine-3-oxide)and its derivatives, Diazoxide(7-chloro-3-methyl-1,2,4-benzothiadiazine-1,1-dioxide) and Phenytoin(5,5-diphenylimidazolidine-2,4 dione); steroidal and non-steroidalanti-inflammatory agents; carotenoids and principally, β-carotene;anti-psoriatic agents such as anthralin and its derivatives and5,8,11,14-eicosatetraynoic and 5,8,11-eicosatriynoic acids, their estersand their amides.

The compositions according to the present invention can also containflavor improving agents, preservatives, stabilizers, humidity regulatingagents, pH regulating agents, osmotic pressure modifying agents,emulsifiers, UV-A and UV-B filters, anti-oxidants such as α-tocopherol,butyl hydroxy anisole or butyl hydroxy toluene.

The following non-limiting examples illustrate the preparation of theactive compounds of Formula I in accordance with the invention as wellas compositions containing these compounds.

EXAMPLE 1 Preparation of 4-[3-(1-adamantyl)-4-methoxy benzamido]methylbenzoate

(a) 3-(1-adamantyl)-4-methoxy benzoic acid

In a round bottom flask there are introduced 5.4 g (225 mmoles) of Mgand 30 ml of tetrahydrofuran. A solution of 48.3 g (150 mmoles) of2-adamantyl-4-bromo anisole, 6 ml (70 mmoles) of dibromoethane in 300 mlof tetrahydrofuran is then added. The reaction mixture is heated toreflux for two hours, cooled to -70° C. and gaseous CO₂ is introducedfor 1 hour. The temperature of the reaction mixture is left to return to20° C., at which point it is poured into water, acidified to pH=1 withconcentrated HCl and extracted with ethyl ether. The organic phase isdecanted, dried over magnesium sulfate and evaporated. Afterrecrystallization in ethyl acetate, 37 g of the expected product (86%yield) having a melting point of 238°-239° C. are obtained.

(b) 3-(1-adamantyl)-4-methoxy benzoyl chloride

In a round bottom flask, there are introduced 200 ml of thionyl chlorideand there are then added, in small fractions, 35 g (122 mmoles) of theacid obtained in stage (a), above. The reaction mixture is heated toreflux until the emission of gases ceases. The reaction mixture isevaporated to dryness, taken up in 100 ml of anhydrous benzene and againevaporated to dryness, yielding 37 g of the expected product (100%yield) having a melting point of 153°-154° C.

(c) 4-[3-(1-adamantyl)-4-methoxy benzamido]methyl benzoate

In a round bottom flask, there are introduced 2.5 g (17 mmoles) ofmethyl p-amino benzoate, 50 ml of tetrahydrofuran and 2.6 ml (18.5mmoles) of triethylamine. There are then slowly added 5.64 g (18.5mmoles) of 3-adamantyl-4-methoxy benzoic acid chloride in 50 ml oftetrahydrofuran. The reaction mixture is stirred at ambient temperaturefor 2 hours, poured into water and extracted with methylene chloride.The organic phase is decanted, dried on magnesium sulfate andevaporated. After recrystallization in a 50:50 isopropyl ether-ethylacetate mixture, 7.1 g of the expected product (92% yield) having amelting point of 179°-180° C. are obtained.

EXAMPLE 2 Preparation of 4-[3-(1-adamantyl)-4-methoxy benzamido]methylbenzoic acid

In a round bottom flask, there are introduced 6 g (14 mmoles) of theester obtained in Example 1 and 200 ml of 2M methanolic NaOH. Thereaction mixture is heated to reflux for 4 hours. It is then evaporatedto dryness, taken up in water, acidified with HCl to pH=1, and extractedwith ether. The organic phase is decanted, dried on magnesium sulfateand evaporated. After recrystyllization in ethyl acetate, 4 g of theexpected acid (69% yield) having a melting point of 286°-287° C. areobtained.

EXAMPLE 3 Preparation of 4-[3-(1-adamantyl)-4-hydroxy benzamido]methylbenzoate

(a) 3-(1-adamantyl)-4-tert.butyl dimethylsilyloxy benzoic acid

In a round bottom flask, there are introduced 1.18 g (48.8 mmoles) ofmagnesium and 20 ml of THF. There are then slowly added 13.7 g (32.5mmoles) of tert.butyl dimethylsilic ether of2-(1-adamantyl)-4-bromophenol, described in European application No.86/400785.1, and the reaction mixture is heated at reflux for 2 hours.It is then cooled to -70° C. and a stream of CO₂ is passed therethroughfor 1 hour. The temperature is permitted to return to 20° C., at whichpoint the reaction mixture is poured into water, acidified withconcentrated HCl to pH=1, and extracted with ethyl ether. The organicphase is decanted washed with water, dried on magnesium sulfate and thesolvents evaporated. The residue is pulverized in 200 ml of isopropylether at reflux. After cooling, the precipitate is filtered, yielding8.20 g (65% yield) of 3-(1-adamantyl)-4-tert. butyl dimethylsilyloxybenzoic acid which melts at 245°-246° C.

(b) 3-(1-adamantyl)-4-tert. butyldimethsilyloxy benzoic acid chloride

6.45 g (16.7 mmoles) of the acid obtained in 3(a), above, are suspendedin 100 ml of CH₂ Cl₂. There are then added 3.3 ml (16.7 mmoles) ofdicyclohexylamine and the reaction mixture is stirred for 1 hour at 20°C. There are then added 1.35 ml (18.4 mmoles) of thionyl chloride. Thereaction mixture is stirred for 2 hours at ambient temperature,evaporated to dryness and taken up in 300 ml of ether. The salt formedis filtered and the ether phase is evaporated, yielding 6.9 g (100%yield) of 3-(1-adamantyl)-4-tert. butyldimethylsilyloxy benzoic acidchloride, in the form of a solid which is used, as is, in the followingsynthesis.

(c) 4-[3-(1-adamantyl)-4-tert.butyl dimethylsilyloxy benzamido]methylbenzoate

In a round bottom flask, there are introduced 2.10 g (13.9 mmoles) ofmethyl p-amino benzoate, 2.10 ml (15.3 mmoles) of triethylamine and 50ml of THF. There are then slowly added 6.20 g (15.3 mmoles) of3-(1-adamantyl)-4-methoxybenzoyl chloride and the reaction mixture isstirred at ambient temperature for 4 hours.

The reaction mixture is poured into water, extracted with methylenechloride, dried on MgSO₄ and the solvents are evaporated. The resultingsolid is recrystallized in a 10:1 diisopropyl ether-ethyl acetatemixture to give 6.5 g (91% yield) of the expected ester which melts at183°-184° C.

(d) 4-[3-(1-adamantyl)-4-hydroxy benzamido]methyl benzoate

In a round bottom flask, there are introduced 6.40 g (12.3 mmoles) ofthe ester obtained in 3(c) above and 75 ml of THF. 13.5 ml (13.5 mmoles)of tetrabutylammonium fluoride (1M in THF) are slowly added. Thereaction mixture is stirred at ambient temperature for 2 hours, thenpoured into water and extracted with methylene chloride. The organicphase is decanted, dried on magnesium sulfate and the solvents areevaporated.

The resulting solid is pulverized in 200 ml of ethyl acetate at reflux,cooled and filtered, yielding 4.20 g (84% yield) of the methyl ester of4-[3-(1-adamantyl)-4-hydroxy benzamido]benzoic acid which melts at305°-306° C.

EXAMPLE 4 Preparation of 4-[3-(1-adamantyl)-4-hydroxy benzamido]benzoicacid

A suspension of 3.3 g (8.1 mmoles) of the ester obtained in 3(d), above,in 100 ml of 2N methanolic NaOH is stirred for 12 hours at ambienttemperature. The reaction mixture is evaporated to dryness, taken up inwater and acidified to pH=0 with concentrated HCl. The resulting solidis filtered, washed with water and dried under a vacuum in the presenceof phosphorous pentoxide (P₂ O₅). The solid is then pulverized in 200 mlof ethyl acetate at reflux. The mixture is cooled to ambient temperatureand the resulting precipitate is filtered, yielding 2.8 g (88% yield) of4-[3-(1-adamantyl)-4-hydroxy benzamido]benzoic acid which melts at348°-249° C.

EXAMPLE 5 Preparation of4-[3-(1-methylcyclohexyl)-4-methoxybenzamido]ethyl benzoate

(a) 4-bromo-2-(1-methylcyclohexyl) phenol

A mixture of methylene cyclohexane (0.96 g, 10 mmoles), p-bromophenol(1.73 g, 10 mmoles) and acid resin (Dowex 50x12-150 mg) is heated at 80°C. for 16 hours. The residue is purified by silica gel chromatography(eluant: 50/50 mixture of CH₂ Cl₂ /hexane). On evaporation of thesolvents 0.50 g (19% yield) of 4-bromo-2-(1-methylcyclohexyl) phenol inthe form of a yellowish oil is obtained.

(b) 4-bromo-2-(1-methylcyclohexyl) anisole

The 4-bromo-2-(1-methylcyclohexyl) phenol (9.26 g, 34.4 mmoles) isdissolved in 50 ml of THF. The solution is cooled to 0° C. and there isadded in small fractions sodium hydride (80% in oil, 1.14 g, 37.8mmoles). The reaction mixture is stirred for 30 minutes at ambienttemperature and 5.37 g (37.8 mmoles) of methyl iodide are slowly added.Stirring is continued for 16 hours at which point water (300 ml) isadded and the reaction mixture is extracted with ether (3×300 ml). Theorganic phase is washed with a saturated sodium bicarbonate solution andthen with a saturated sodium chloride solution. The reaction mixture isdried on MgSO₄, filtered and the solvents are evaporated. The residue ispurified by chromatography on a silica column, eluted by a 20/80 mixtureof dichloromethane and hexane, yielding 9 g (92% yield) of4-bromo-2-(1-methylcyclohexyl) anisole in the form of a colorless oil.

(c) 3-(1-methylcyclohexyl)-4-methoxy benzoic acid

The compound obtained in 5(b), above, (9.0 g, 31.8 mmoles) is dissolvedin 50 ml of dry THF. The resulting solution is slowly added to magnesium(850 mg, 35 mmoles) and an iodine crystal. The reaction mixture isheated to reflux after the addition of the first 5 milliliters ofsolution. Reflux is maintained for 15 minutes after the addition isterminated. The reaction mixture is then cooled to -40° C. and a streamof CO₂ is passed therethrough for one hour. The mixture is poured into6N HCl, and extracted with ether (3×300 ml). The organic phase is washedwith water until neutral, dried on MgSO₄ and evaporated. The resultingresidue is pulverized in hexane, filtered and dried, yielding 6.50 g(82% yield) of 3-(1-methylcyclohexyl)-4-methoxy benzoic acid which meltsat 199° C.

(d) 3-(1-methylcyclohexyl)-4-methoxy benzoyl chloride

In a round bottom flask, there are introduced 4.96 g (20 mmoles) of3-(1-methylcyclohexyl)-4-methoxy benzoic acid, 75 ml of dichloromethane,and 4 ml (20 mmoles) of dicyclohexylamine. The reaction mixture isstirred for 1 hour. To the resulting solution, there are added 1.45 ml(20 mmoles) of thionyl chloride (SOCl₂) and the mixture is stirred for 2hours at ambient temperature. The reaction mixture is then evaporated todryness and taken up in 200 ml of ether. The dicyclohexyl-ammoniumchloride is filtered off and the solvent is evaporated, yielding 5.30 g(100% yield) of crude 3-(1-methylcyclohexyl)-4-methoxy benzoyl chloridewhich is used, as is, for the following synthesis:

(e) 4-[3-(1-methylcyclohexyl)-4-methoxy benzamido]ethyl benzoate

In a round bottom flask, there are introduced 3.3 g (20 mmoles) of ethylp-aminobenzoate, 3.1 ml (20 mmoles) of triethylamine and 75 ml of THF.5.3 g (20 mmoles) of the acid chloride obtained in 5(d), above, in 50 mlof THF are slowly added and the mixture is stirred at ambienttemperature for 2 hours. The reaction mixture is poured into water andextracted with methylene chloride. The organic phase is decanted, driedon MgSO₄ and the solvents are evaporated, yielding 6.30 g (80% yield) of4-[3-(1-methylcyclohexyl)-4-methoxy benzamido]ethyl benzoate in the formof an oil.

EXAMPLE 6 Preparation of4-[3-(1-methylcyclohexyl)-4-methoxybenzamido]benzoic acid

In a round bottom flask, there are introduced 5.20 g (13.1 mmoles) ofthe ester obtained in 5(e), above, and 150 ml of 2N methanolic NaOH. Thereaction mixture is stirred at ambient temperature for 24 hours,evaporated to dryness, taken up in water, acidified to pH=0 withconcentrated HCl, extracted with ether, dried on MgSO₄ and evaporated.The residue is recrystallized in an 8/2 mixture of isopropyl ether andethyl acetate, yielding 3.9 g (82% yield) of4-[3-(1-methylcyclohexyl)-4-methoxybenzamido]benzoic acid which melts at230°-231° C.

EXAMPLE 7 Preparation of 4-[3-(1-adamantyl)-4-decyloxy benzamido]methylbenzoate

2.00 g (5 mmoles) of the ester obtained in 3(d), above, are dissolved in70 ml of dimethyl formamide (DMF) and added slowly to a suspension ofsodium hydride (80% in oil, 150 mg, 5 mmoles) in 20 ml of DMF. Thereaction mixture is stirred at ambient temperature until the emission ofgases ceases. 1.1 ml (5 mmoles) of 1-iododecane are added and thereaction mixture is stirred for 4 hours at ambient temperature. Thereaction mixture is poured into water and extracted with ether. Theorganic phase is decanted, washed with water, dried on MgSO₄ and thesolvents evaporated. The residue is purified by chromatography on asilica column (eluant: CH₂ Cl₂), yielding 2.5 g (92% yield) of4-[3-(1-adamantyl)-4-decyloxy benzamido]methyl benzoate which melts at106°-107° C.

EXAMPLE 8 Preparation of 4-[3-(1-adamantyl)-4-decyloxy benzamido]benzoicacid

In a manner analogous to that of Example 4, 2.00 g (3.67 mmoles) of theester obtained in Example 7, treated for 48 hours with 100 ml of 2Nmethanolic NaOH produces 1.8 g (95% yield) of4-[3-(1-adamantyl)-4-decyloxybenzamido]benzoic acid which melts at247°-248° C.

EXAMPLE 9 Preparation of 4-[3-(1-adamantyl)-4-hexyloxy benzamido]methylbenzoate

In a manner analogous to that of Example 7, starting with 2.50 g (6.2mmoles) of the ester obtained in Example 3(d), above, treated with 187mg (6.2 mmoles) of sodium hydride (80% in oil) and 0.9 ml (6.2 mmoles)of 1-iodohexane, there are obtained 2.9 g (96% yield) of4-[3-(1-adamantyl)-4-hexyloxy benzamido]methyl benzoate which melts at154°-155° C.

EXAMPLE 10 Preparation of 4-[3-(1-adamantyl)-4-hexyloxybenzamido]benzoic acid

In a manner analogous to Example 8, starting with 2.27 g (4.6 mmoles) ofthe ester obtained in Example 9, there are obtained 2.10 g (96% yield)of 4-[3-(1-adamantyl)-4-hexyloxy benzamido]benzoic acid which melts at256°-257° C.

EXAMPLE 11 Preparation of 4-[3-(1,1-dimethyldecyl)-4-methoxybenzamido]methyl benzoate

(a) 4-bromo-2-(1,1-dimethyldecyl) phenol

A mixture of p-bromophenol (25.85 g, 149 mmoles) and 2-methylundec-1-ene(25.15 g, 149 mmoles) is stirred at 110° C. for 48 hours in the presenceof an acid resin (Dowex 50×12, 3 g). The resulting mixture is purifiedby chromatography on a silica column (eluant: 50/50 mixture ofdichloromethane and hexane), yielding 25.04 g (49% yield) of4-bromo-2-(1,1-dimethyldecyl) phenol in the form of a light yellow oil.

(b) 4-bromo-2-(1,1-dimethyldecyl) anisole

To a solution of the phenol obtained in Example 11(a), above, (24.88 g,72.9 mmoles) in THF (200 ml), there are added, in small portions, 2.19 g(72.9 mmoles) of sodium hydride (80% in oil). Once the addition iscompleted, the reaction mixture is stirred for 1 hour at ambienttemperature at which point methyl iodide (10.35 g, 72.9 mmoles) isslowly added. The reaction mixture is stirred for 2 hours at ambienttemperature, the solvent is evaporated, water (300 ml) is added and thereaction mixture is extracted with ether (3×200 ml). The organic phaseis washed with a saturated sodium chloride solution, dried on MgSO₄ andthe solvents evaporated, yielding 22.2 g (86% yield) of4-bromo-2-(1,1-dimethyldecyl) anisole in the form of a yellow oil.

(c) 3-(1,1-dimethyldecyl)-4-methoxy benzoic acid

The 4-bromo-2-(1,1-dimethyldecyl) anisole (15.72 g, 44.2 mmoles)obtained in Example 11(a), above, is dissolved in THF (50 ml). Thissolution is slowly added to magnesium (1.18 g, 48.7 mmoles) and aniodine crystal, while being maintained at reflux by heating. Once theaddition is complete, the reaction mixture is maintained at reflux for30 minutes and then cooled to -40° C. 300 ml of THF are added and astream of CO₂ is passed therethrough for 2 hours. The reaction mixtureis then poured into a solution of HCl (4N, 300 ml) and the product isextracted with ether (3×300 ml). The organic phase is washed with wateruntil neutral, dried on MgSO₄, and the solvents are evaporated. Theresidue is pulverized in isooctane to produce 7.25 g (51%. yield) of3-(1,1-dimethyldecyl)-4-methoxy benzoic acid which melts at 112° C.

(d) 3-(1,1-dimethyldecyl)-4-methoxy benzoyl chloride

The acid obtained in Example 11(c), above, (7.18 g, 22.4 mmoles) issuspended in 200 ml of dichloromethane. Dicyclohexylamine (40.6 g, 22.4mmoles) is slowly added and the mixture is cooled to 0° C. Thionylchloride (2.66 g, 22.4 mmoles) is added and the reaction mixture isstirred for 16 hours at ambient temperature. The precipitate which formsis filtered and the solvent evaporated, thus yielding, quantitatively,crude 3-(1,1-dimethyldecyl)-4-methoxybenzoyl chloride in the form of awhite solid which is used, as is, for the following synthesis.

(e) 4-[3-(1,1-dimethyldecyl)-4-methoxybenzamido]methyl benzoate

All of the acid chloride obtained in Example 11(d), above, is dissolvedin 50 ml of THF. The resulting solution is added to a solution of methylp-aminobenzoate (3.39 g, 22.4 mmoles) and triethylamine (2.27 g, 22.4mmoles) in THF (150 ml). The reaction mixture is stirred for 1 hour atambient temperature. The resulting precipitate is filtered and thesolvent is evaporated. The product is purified by column chromatography(eluant: dichloromethane). The solvents are evaporated and the resultingsolid is pulverized in hexane, filtered and dried, yielding 7.72 g (76%yield) of 4-[3-(1,1-dimethyldecyl) -4-methoxybenzamido]methyl benzoatewhich melts at 120° C.

EXAMPLE 12 Preparation of 4-[3-(1,1-dimethyldecyl)-4-methoxybenzamido]benzoic acid

The ester obtained in Example 11(e), above, (2.5 g, 5.51 moles) is mixedwith 110 ml of methanol. 11 ml of 5N NaOH are added and the reactionmixture is stirred for three days. The methanol is evaporated and 4N HCl(200 ml) is added. The product is extracted with dichloromethane (3×300ml). The organic phase which is washed with a saturated sodiumbicarbonate solution and then with sodium chloride, is dried over MgSO₄and the solvent is evaporated. The resulting solid is pulverized inhexane, filtered and then dried, yielding 1.57 g (65% yield) of4-[3-(1,1-dimethyldecyl)-4-methoxybenzamido]benzoic acid which melts at177° C.

EXAMPLE 13 Preparation of 4-(3-tert.butyl-4-methoxy benzamido) methylbenzoate

Crude 3-(tert.butyl)-4-methoxy) benzoic acid chloride prepared from10.14 g (50 mmoles) of 3-(tert.butyl)-4-methoxy benzoic acid describedin French patent application No. 85.13747 (2.570.377), is dissolved in60 ml of THF. The solution is added slowly over a mixture of methyl4-aminobenzoate (7.14 g, 47.2 mmoles) and triethylamine (4.78 g, 47.2mmoles), in solution in THF (50 ml). The reaction mixture is stirred for3 hours at ambient temperature. The precipitate that forms is filteredand the solvents are evaporated. 300 ml of water are added and theproduct is extracted with ether (3×200 ml).

The organic phase which is washed with a saturated sodium bicarbonatesolution and then with sodium chloride is dried on MgSO₄, filtered andthe solvents are evaporated. The resulting solid is recrystallized inhexane containing about 5% methanol, yielding 14.02 g (87% yield) of4-(3-tert.butyl-4-methoxybenzamido) methyl benzoate.

EXAMPLE 14 Preparation 4-(3-tert.butyl-4-methoxy benzamido) benzoic acid

In a manner analogous to that of Example 4, starting with 5 g (14.65mmoles) of the ester obtained in Example 13, above, 4.27 g (89%) yieldof 4-(3-tert.butyl-4-methoxybenzamido) benzoic acid, which melts at 250°C., are obtained.

EXAMPLE 15 Preparation ofN-[4-[3-(1-adamantyl)-4-methoxybenzamido]-benzoyl]pyrrolidine

1.7 g (9 mmoles) of N-p-aminobenzoyl pyrrolidine and 1 g (10 mmoles) oftriethylamine are dissolved in 30 ml of dichloromethane. With stirring,2.8 g (9 mmoles) of 3-(1-adamantyl)-4-methoxybenzoyl chloride dissolvedin 60 ml of dichloromethane are added. The reaction mixture is stirredfor 16 hours, at which point water is added and the reaction mixture isextracted with dichloromethane. The extract is washed with water,extracted with methylene chloride and dried on MgSO₄. The solvents areevaporated and the residue (yellow foam) is crystallized in ethylacetate to give 3.0 g (73% yield) of N-[4-[3-(1-adamantyl)-4-methoxybenzamido]-benzoyl]pyrrolidine which melts at 239°-242° C.

EXAMPLE 16 Preparation ofN-[4-[3-(1-adamantyl)-4-methoxybenzamido]-benzoyl]piperidine

In a manner analogous to that of Example 15, above, starting with 0.7 g(3.6 mmoles) of N-[4-amino benzoyl]piperidine, 1.0 g (63% yield) ofN-[4-[3-(1-adamantyl)-4-methoxybenzamido]-benzoyl]piperidine isobtained.

EXAMPLE 17 Preparation of N-[4-[3-(1-adamantyl)-4-methoxy benzamido]benzoyl] morpholine

In a manner analogous to that of Example 15, above, starting with 3.0 g(15 mmoles) of N-[4-aminobenzoyl]morpholine, -5.6 g (81% yield) of4-[3-(1-adamantyl)-4-methoxy benzamido]benzoyl]morpholine which melts at238°-241° C. are obtained.

EXAMPLE 18 Preparation of N-[4-[3-(1-adamantyl)-4-methoxybenzamido]benzoyl]tert. butylamine

Starting with 1.0 g (5 mmoles) of N-tert.butyl-4-aminobenzamide, 1.5 g(63% yield) of N-[4-[3-(1-adamantyl)-4-methoxy benzamido ]benzoyl]tert.butylamine which melts at 270°-273° C. are obtained. E7

(a) 4-[3-(1-adamantyl)-4-methoxy benzamido]benzoic acid chloride

2.0 g (5 mmoles) of 4-[3-(1-adamantyl)-4-methoxy benzamido]benzoic acidare dissolved in 60 ml of THF. 1.1 g (6 mmoles of dicyclohexylamine areslowly added. A white precipitate is immediately formed. The reactionmixture is then cooled to 0° C. and 0.7 g (6 mmoles) of thionyl chlorideis slowly added. The reaction mixture is stirred for 3 hours at ambienttemperature. The solid that forms is filtered and then the filtrate isevaporated. The resulting residue is used, as is, in the followingsynthesis.

(b) N-[4-[3-(1-adamantyl)-4-methoxy benzamido]benzoyl]ethylamine

The crude acid chloride obtained in Example 19(a), above, is dissolvedin 80 ml of THF. There is then slowly added a solution of ethylamine(0.5 g, 11 mmoles) in dry THF 20 ml). The reaction mixture is stirredfor 16 hours at ambient temperature, filtered and the filtrate isevaporated. The reddish residue thus obtained is recrystallized inethanol to give 0.5 g (24% yield) of N-[4-[3-(1-adamantyl)-4-methoxybenzamido]benzoyl]ethylamine which melts at 274°-277° C.

EXAMPLE 20 N-[4-[3-(1-adamantyl)-4-methoxy benzamido]benzoyl]aniline

This compound is obtained in accordance with the same procedures asthose described in Example 19. 0.7 g (30% yield) of the expected productwhich melts at 265°-268° C. is obtained.

EXAMPLE 21 Preparation of the benzyl amide of4-[3-(1-adamantyl)-4-methoxy benzamido]benzoic acid

This compound is obtained in accordance with the same procedures asthose described in Example 19. 0.2 g (9% yield) of the expected productwhich melts at 279°-280° C. is obtained.

EXAMPLE 22 Preparation of 4-[3-(1-adamantyl)-4-methoxybenzamido]2-hydroxy ethyl benzoate

The crude acid chloride obtained in Example 19(a), above, starting with2 g of 4-[3-(1-adamantyl)-4-methoxy benzamido]benzoic acid is dissolvedin a solution of ethylene glycol (1.4 g, 22 mmoles) and pyridine (0.8 g,10 mmoles) in dry THF (20 ml). The reaction mixture is stirred for 16hours at ambient temperature and is then filtered. The filtrate isevaporated to dryness to give a yellowish residue that is purified bycolumn chromatography by using as the eluant a 1/1 mixture ofdichloromethane and ethyl acetate. The solvents are evaporated, yielding1.2 g (55% yield) of the expected ester which melts at 201°-203° C.

EXAMPLE 23 Preparation of N-(4-acetyl phenyl)-3-(1-adamantyl)-4-methoxybenzamide

A solution of 5.7 g of 3-(1-adamantyl)-4-methoxy benzoyl chloride,obtained in Example 1(b), above, in dichloromethane (60 ml) is slowlyadded to a mixture of 4-aminoacetophenone (2.6 g, 19 mmoles) andtriethylamine (2.1 g, 21 mmoles) in dichloromethane (30ml). The mixtureis stirred for 16 hours then poured into water and extracted withdichloromethane. The organic phase is recovered, washed with water,dried on magnesium sulfate, then evaporated. The resulting residue isrecrystallized in ethylacetate, yielding 3.0 g (39% yield) ofN-(4-acetyl phenyl)-3-(1-adamantyl)-4-methoxybenzamide in the form ofwhite crystals having a melting point of 200°-201° C.

EXAMPLE 24 Preparation of N-[4-(1-hydroxy ethyl)phenyl]-3-(1-adamantyl)-4-methoxy benzamide

The amide obtained in Example 23, above, (0.9 g, 2 mmoles) is dissolvedin methanol (25 ml) and treated with 0.12 g (3 mmoles) of sodiumborohydride. The mixture is stirred at ambient temperature for 2 days,poured into water and extracted with ether. The extracts are dried onmagnesium sulfate, then the solvent is evaporated. The resulting residueis recrystallized in ethyl acetate to giveN[4-[1-hydroxyethyl)phenyl]-3-(1-adamantyl)-4-methoxy benzamide (0.5 g,66% yield) having a melting point of 207°-209° C.

EXAMPLE 25 Preparation of N-[4-[3-(1-adamantyl)-4-methoxybenzamido]benzoyl]2-hydroxyethylamine

In a manner analogous to that of Example 19, above, theN-[4-[3-(1-adamantyl)-4-methoxy benzamido]benzoyl]2-hydroxyethylamine isobtained (1.1 g, 50% yield) which melts at 265°-268° C. (crystallized inan ethanol-ether mixture).

EXAMPLE 26 Preparation of 2-hydroxy-4-[3-(1-adamantyl)-4-methoxybenzamido]methyl benzoate

(a) methyl 4-amino-2-tert.butyl dimethylsilyloxy benzoate

2.0 g (12 mmoles) of methyl 4-amino-2-hydroxy benzoate are dissolved in30ml of dimethylformamide (DMF) containing 2.8 g (28 mmoles) oftriethylamine, and 70 mg (0.6 mmoles) of 4-N,N-dimthylamino pyridine. Asolution of tert.butyl dimethylsilyl chloride (4.2 g, 28 mmoles) in 40ml of DMF is slowly added. The reaction mixture is stirred for 2 days atambient temperature and is then heated at 100° C. for 8 hours. The DMFis evaporated under a vacuum; water is added; and the reaction mixtureis extracted with ether. The organic phase is recovered, dried and thesolvent evaporated, yielding crude methyl 4-amino-2-tert.butyldimethylsilyoxy benzoate which is used, as is, in the followingsynthesis.

(b) 2-tert.butyl dimethylsilyloxy-4-[3-(1-adamantyl)-4-methoxybenzamido]methyl benzoate

The crude methyl 4-amino-2-tert.butyl dimethylsilyloxy benzoate ofExample 26(a) above, (3.0 g, 10 mmoles) is dissolved in 20 ml of dry THFcontaining 1.1 g (10 mmoles) of triethylamine. A solution of4-methoxy-3-(1-adamantyl) benzoyl chloride in 80 ml of dry THF is slowlyadded and the reaction mixture is stirred for 16 hours at 20° C. Thereaction mixture is then evaporated to dryness, taken up in 100 ml ofdichloromethane, washed with water, dried on MgSO₄ and evaporated todryness. The resulting residue is recrystallized in anethanol/ethylether mixture, yielding 2.7 g (48% yield) of 2-tert.butyldimethylsilyloxy -4-[3-(1-adamantyl)-4-methoxy benzamido]methyl benzoatewhich melts at 225°-227° C.

(c) 2-hydroxy-4-[3-(1-adamantyl)-4-methoxy benzamido]methyl benzoate

2.7 g (5 mmoles) of the ester obtained in Example 26(b), above, aredissolved in 80 ml of THF. A 1M solution of tetrabutyl ammonium fluoridein THF (6 ml) is added and the reaction mixture is stirred for 16 hoursat 20° C. (the formation of a white precipitate is observed). Thereaction mixture is evaporated to dryness, water is added and thereaction mixture is extracted with ether (3×100 ml). The extract isdried on MgSO₄ and evaporated to dryness (2.0 g, 95% yield); the residueis crystallized by the addition of a small amount of ether, thusyielding 2-hydroxy-4-[3-(1-adamantyl)-4-methoxy benzamido]methylbenzoate (1.6 g, 76% yield) which melts at 207°-209° C.

Examples of Compositions

A. Orally Administrable Compositions

    ______________________________________                                        Example (a) - 0.2 g tablet                                                    4-[3-(1-adamantyl)-4-methoxy                                                                            0.001  g                                            benzamido]methyl benzoate                                                     Starch                    0.114  g                                            Dicalcium phosphate       0.020  g                                            Silica                    0.020  g                                            Lactose                   0.030  g                                            Talc                      0.010  g                                            Magnesium stearate        0.005  g                                            Example (b) - Drinkable suspension in 5 ml ampoules                           4-[3-(1-adamantyl)-4-methoxy benzamido]                                                                 0.001  g                                            benzoic acid                                                                  Glycerine                 0.500  g                                            Sorbitol, 70%             0.500  g                                            Sodium saccharinate       0.010  g                                            Methyl parahydroxybenzoate                                                                              0.040  g                                            Flavoring, sufficient amount                                                  Purified water, sufficient amount for                                                                   5      ml                                           ______________________________________                                    

B. Topically Administrable Compositions

    ______________________________________                                        Example (a) - Ointment                                                        4-[3-(1-adamantyl)-4-methoxy benzamido]                                       benzoic acid              0.020   g                                           Isopropyl myristate       81.700  g                                           Fluid petrolatum oil      9.100   g                                           Silica, sold under the trade designation                                      "Aerosil 200" by Degussa  9.180   g                                           Example (b) - Anhydrous hydrophobic ointment                                  4-[3-(1,1-dimethyldecyl)-4-methoxy                                                                      0.10    g                                           benzamido]benzoic acid                                                        White petrolatum          49.95   g                                           Triglycerides of capric and caprylic                                                                    49.95   g                                           acids sold under the trade designation                                        "Miglyol 812" by Dynamit Nobel                                                ______________________________________                                    

This ointment is obtained by mixing the petrolatum and "Miglyol 812" at70° C. The active component is then introduced into the mixture by verycarefully dispersing it with an ultrasonic bath by heating to 40°-50° C.The resulting ointment is then cooled with stirring.

In this Example, the active component (0.10 g) can be replaced by 0.5 gof 4-[3-(1-adamantyl)-4-hexyloxybenzamido]benzoic acid.

    ______________________________________                                        Example (c) - Lotion                                                          ______________________________________                                        4-[3-(1-methylcyclohexyl)-4-methoxy                                                                    0.01   g                                             benzamido] benzoic acid                                                       Absolute ethanol         30.00  g                                             Polyethylene glycol (400)                                                                              69.99  g                                             ______________________________________                                    

This lotion is obtained by mixing the polyethylene glycol (400) andethanol. The active component is introduced and dissolved therein in anultrasonic bath.

    ______________________________________                                        Example (d) - Oil-in-water anionic emulsion                                   ______________________________________                                        Sodium lauryl sulfate   0.784    g                                            1,2-propanediol         1.570    g                                            White petrolatum        19.502   g                                            Cetyl alcohol           19.504   g                                            Methyl parahydroxy benzoate                                                                           0.076    g                                            Propyl parahydroxy benzoate                                                                           0.074    g                                            N-[4-[3-(1-adamantyl)-4-methoxy benzamido]                                                            0.500    g                                            benzoyl] morpholine                                                           Sterile water, sufficient amount for                                                                  100.00   g                                            ______________________________________                                    

This emulsion is obtained by preparing the following A and B mixtures:

Mixture A

Sodium lauryl sulfate

1,2-propanediol

Methyl parahydroxy benzoate

Sterile water

After having dissolved the methyl parahydroxy benzoate with ultrasonicstirring, the mixture is heated to 70° C.

Mixture B

White petrolatum

Cetyl alcohol

Propyl parahydroxy benzoate

After having dissolved the propyl parahydroxy benzoate with ultrasonicstirring, the mixture is also heated to 75° C.

The emulsion is then formed by pouring Mixture A into Mixture B. Aftercooling to ambient temperature, the active component is introduced andthe mixture is carefully stirred to thoroughly homogenize it. Afterpackaging the emulsion, it is passed to a triclinder.

C. Cosmetic Compositions

    ______________________________________                                        Example (a) - Non-oily fluid cream                                            ______________________________________                                        4-[3-(1-adamantyl)-4-hexyloxy benzamido]                                                                1.00    g                                           methyl benzoate           1.00    g                                           Palmito stearate of ethylene glycol and                                                                 20.00   g                                           polyoxyethylenated glycol                                                     Saturated glycerides of poly oxyethylenated                                   and glycolized C.sub.10 -C.sub.18                                                                       3.00    g                                           Fluid petrolatum oil      3.00    g                                           Preservatives             0.05    g                                           Water, sufficient amount for                                                                            100.00  g                                           ______________________________________                                    

This cream is obtained by heating to 70° C. a mixture of the palmitostearate of ethylene glycol and polyoxyethylenated glycol, the saturatedglycerides of polyoxyethylenated and glycolized C₁₀ -C₁₈ and thepetrolatum oil. The active component is then introduced and carefullydispersed therein. Water and the preservatives, also at a temperature of70° C., are then poured into the above oily phase and stirring iscontinued until the temperature returns to ambient temperature and anemulsion is obtained.

In this Example, the active component can be replaced by the same amountof the morpholide of 4-[3-(1-adamantyl)-4-methoxy benzamido]benzoicacid.

    ______________________________________                                        Example (b) - Cream with slightly oily consistency                            ______________________________________                                        4-(3-tert.butyl-4-methoxy benzamido)                                                                   1.00    g                                            benzoic acid                                                                  Mixture of mono and diglycerides of                                                                    15.00   g                                            palmitic and stearic acids                                                    Sorbitan monostearate    4.00    g                                            Sorbitan monostearate    1.20    g                                            polyoxyethylenated with 20                                                    moles of ethylene oxide                                                       Fluid petrolatum oil     10.00   g                                            Preservatives            0.04    g                                            Water, sufficient amount for                                                                           100.00  g                                            ______________________________________                                    

This cream is obtained in accordance with the same procedures as thosedescribed above.

In this Example, the active component can be replaced by the same amountof N-[4-[3-(1-adamantyl)-4-methoxy benzamido]benzoyl]ethylamine.

    ______________________________________                                        Example (c) - Sun protection oil                                                   4-[3-(1-adamantyl)-4-decyloxy benzamido]                                                               0.50    g                                            methyl benzoate                                                               2-octyl dodecanol        42.00   g                                            Triglycerides of capric and                                                                            40.00   g                                            caprylic acids                                                                Mixture of the esters of capric and                                                                    17.50   g                                            caprylic acids with saturated fatty                                           C.sub.12 -C.sub.18 alcohols                                                   Example (d) - Alcoholic lotion for the scalp                                  4-(3-tert.butyl-4-methoxybenzamido)                                                                    0.80    g                                            benzoic acid                                                                  Ethanol, 95%             83.00   g                                            Water, sufficient amount for                                                                           100.00  g                                            Example (e) - 2 stage shampoo to be mixed at                                  the time of use                                                          (i)  Treating stage                                                                4-[3-(1-adamantyl)-4-decyloxy benzamido]                                                               0.50    g                                            methyl benzoate                                                               2-octyl dodecanol        50.00   g                                            Triglycerides of capric and                                                   caprylic acids           49.50   g                                       (ii) Washing stage                                                                 Sodium lauryl ether sulfate                                                                            50.00   g                                            Glycerol cocoate polyoxyethylenated                                                                    5.00    g                                            with 7 moles of ethylene oxide                                                Preservatives            0.05    g                                            Water, sufficient amount for                                                                           100.00  g                                       ______________________________________                                    

At the moment of use, 10 g of the treating stage composition is mixedwith 90 g of the washing stage composition.

What is claimed is:
 1. An aromatic benzamido compound having the formula##STR7## wherein R₁ represents --COR₅ wherein R₅ represents --OR₆wherein R₆ represents hydrogen, lower alkyl or mono- orpolyhydroxyalkyl,R₂ represents 1-adamantyl, R₃ represents alkyl having1-10 carbon atoms, R₄ represents hydrogen, lower alkyl or hydroxy, andthe pharmaceutically or cosmetically acceptable salts of said aromaticbenzamido compound of Formula I when R₆ represents hydrogen.
 2. Thearomatic benzamido of claim 1 which is 40[3-(1-adamantyl)-4-methoxybenzamido]benzoic acid.
 3. A compound selected from the group consistingof:4-[3-(1-adamantyl)-4-methoxy benzamido]benzoic acid,4-[3-(1-adamantyl)-4-methoxy benzamido]methyl benzoate,N-[4-[3-(1-adamantyl)-4-methoxy benzamido]benzoyl]ethylamine,4-[3-(1-adamantyl)-4-hydroxy benzamido]benzoic acid,4-[3-(1-adamantyl)-4-hydroxy benzamido]methyl benzoate,4-[3-(1-methylcyclohexyl)-4-methoxy benzamido]benzoic acid,4-[3-(1-methylcyclohexyl)-4-methoxy benzamido]ethyl benzoate,4-[3-(1-adamantyl)-4-decyloxy benzamido]benzoic acid,4-[3-(1-adamantyl)-4decyloxy benzamido]methyl benzoate,4-[3-(1-adamantyl)-4-hexyloxy benzamido]benzoic acid,4-[3-(1-adamantyl)-4-hexyloxy benzamido]methyl benzoate,4-[3-(1,1-dimethyl decyl)-4-methoxy benzamido]benzoic acid,4-[3-(1,1-dimethyl decyl)-4-methoxy benzamido]methyl benzoate,4-(3-tert. butyl-4-methoxy benzamido) benzoic acid, 4-(3-tert.butyl-4-methoxy benzamido) methyl benzoate,N-[4-[3-(1-adamantyl)-4-methoxy benzamido]benzoyl]pyrrolidine,N-[4-[3-(1-adamantyl)-4-methoxy benzamido]benzoyl]piperidine,N-[4-[3-(1-adamantyl)-4-methoxy benzamido]benzoyl]morpholine,N-[4-[3-(1-adamantyl)-4-methoxy benzamido]benzoyl]tert. butylamine,N-[4-[3-(1-adamantyl)-4-methoxy benzamido]benzoyl]ethylamine,N-[4-[3-(1-adamantyl)-4-methoxy benzamido]benzoyl]aniline,N-[4-[3-(1-adamantyl)-4-methoxy benzamido]benzoyl]benzylamine,4-[3-(1-adamantyl)-4-methoxy benzamido]2-hydroxyethyl benzoate,N-(4-acetylphenyl)-3-(1-adamantyl)-4-methoxy benzamide,N-[4-(1-hydroxyethyl) phenyl]-3-(1-adamantyl)-4-methoxy benzamide,N-[4-[3-(1-adamantyl)-4-methoxy benzamido]benzoyl]2-hydroxyethylamineand 2-hydroxy-4-[3-(1-adamantyl)-4-methoxy benzamido]methyl benzoate.